The role of kinetic context in apparent biased agonism at GPCRs

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that ‘kinetic context’, as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism

eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5'UTR

Background: Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Results: Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5′UTR of target mRNAs directly upstream of the AUG start codon. Conclusions: Our data support a model whereby purine motifs towards the 3′ end of the 5′UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding

Further investigation of the impact of idealised continents and SST distributions on the Northern Hemisphere storm tracks

Building on studies by Brayshaw et al. (2009, 2011) of the basic ingredients of the North Atlantic storm track (land-sea contrast, orography and SST), this article investigates the impact of Eurasian topography and Pacific SST anomalies on the North Pacific and Atlantic storm tracks through a hierarchy of atmospheric GCM simulations using idealised boundary conditions in the HadGAM1 model. The Himalaya-Tibet mountain complex is found to play a crucial role in shaping the North Pacific storm track. The northward deflection of the westerly flow around northern Tibet generates an extensive pool of very cold air in the north-eastern tip of the Asian continent, which strengthens the meridional temperature gradient and favours baroclinic growth in the western Pacific. The Kuroshio SST front is also instrumental in strengthening the Pacific storm track through its impact on near-surface baroclinicity, while the warm waters around Indonesia tend to weaken it through the impact on baroclinicity of stationary Rossby waves propagating poleward from the convective heating regions. Three mechanisms by which the Atlantic storm track may be affected by changes in the boundary conditions upstream of the Rockies are discussed. In the model configuration used here, stationary Rossby waves emanating from Tibet appear to weaken the North Atlantic storm track substantially, whereas those generated over the cold waters off Peru appear to strengthen it. Changes in eddy-driven surface winds over the Pacific generally appear to modify the flow over the Rocky Mountains, leading to consistent modifications in the Atlantic storm track. The evidence for each of these mechanisms is, however, ultimately equivocal in these simulations

Goytisolo, la voz que mira

Publicat a La Verdad